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The Journal of Neuroscience, June 20, 2007, 27(25):6852-6857; doi:10.1523/JNEUROSCI.0933-07.2007

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Neurobiology of Disease
Distinct Functional Domains of Neurofibromatosis Type 1 Regulate Immediate versus Long-Term Memory Formation

Ivan Shun Ho,^1,2 * Frances Hannan,^1,3 * Hui-Fu Guo,^1,4 Inessa Hakker,¹ and Yi Zhong¹

¹Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, ²Graduate Program in Genetics, State University of New York at Stony Brook, Stony Brook, New York 11794, ³New York Medical College, Valhalla, New York 10595, and ⁴Blanchette Rockefeller Neuroscience Institute, Rockville, Maryland 20852

Correspondence should be addressed to Y. Zhong at the above address. Email: zhongyi{at}cshl.edu

Neurofibromatosis type 1 (NF1) is a dominant genetic disorder that causes tumors of the peripheral nervous system. In addition, >40% of afflicted children have learning difficulties. The NF1 protein contains a highly conserved GTPase-activating protein domain that inhibits Ras activity, and the C-terminal region regulates cAMP levels via G-protein-dependent activation of adenylyl cyclase. Behavioral analysis indicates that learning is disrupted in both Drosophila and mouse NF1 models. Our previous work has shown that defective cAMP signaling leads to the learning phenotype in Drosophila Nf1 mutants. In the present report, our experiments showed that in addition to learning, long-term memory was also abolished in Nf1 mutants. However, altered NF1-regulated Ras activity is responsible for this defect rather than altered cAMP levels. Furthermore, by expressing clinically relevant human NF1 mutations and deletions in Drosophila Nf1-null mutants, we demonstrated that the GAP-related domain of NF1 was necessary and sufficient for long-term memory, whereas the C-terminal domain of NF1 was essential for immediate memory. Thus, we show that two separate functional domains of the same protein can participate independently in the formation of two distinct memory components.

Key words: neurofibromatosis type 1; long-term memory; learning; Drosophila; cognitive disorder; human disease

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Received March 1, 2007; revised May 8, 2007; accepted May 11, 2007.

Correspondence should be addressed to Y. Zhong at the above address. Email: zhongyi{at}cshl.edu

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